Mifepristone (RU-486) has both antiprogesterone and antiglucocorticoid properties. The antiglucocorticoid effect results in a clinically significant pharmacological consequence in patients with Cushing's syndrome, which is:

• A Reduced ACTH production from pituitary due to enhanced negative feedback
• B Blockade of glucocorticoid receptors leading to clinical improvement despite very high cortisol levels, with reflexively elevated ACTH and cortisol ✓
• C Inhibition of adrenal 11β-hydroxylase, reducing cortisol synthesis
• D Enhanced hepatic clearance of cortisol via CYP3A4 induction

Explanation

Mifepristone blocks the glucocorticoid receptor (GR), preventing cortisol from exerting its effects at the tissue level — this provides clinical improvement in Cushing's syndrome symptoms. However, GR blockade also removes cortisol's negative feedback on the hypothalamo-pituitary axis, causing reflex elevation of CRH, ACTH, and consequently cortisol levels. Thus, laboratory cortisol will be high (cannot be used to monitor response) but clinical symptoms improve. It is approved for Cushing's syndrome with hyperglycemia. Metyrapone and ketoconazole inhibit adrenal synthesis (option C).

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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